Comparation of predictive value of CAT and change in CAT in the short term for future exacerbation of chronic obstructive pulmonary disease

Abstract Purpose Our study aimed to compare the predictive value of the COPD Assessment Test (CAT) score at baseline and short-term change in CAT for future exacerbations in chronic obstructive pulmonary disease (COPD) patients. Methods This was a multicentre prospective study. Patients with COPD were recruited into the study and followed up for one year. CAT score and exacerbation in the previous year were collected at baseline. Change in CAT was defined as CAT score changing between baseline and the 6-month follow-up. Exacerbation was recorded during the one-year follow-up from 0th to 12th month. Result A total of 536 patients were enrolled for final analysis. The mean baseline CAT score was 14.5 ± 6.6 and the median (IQR) change in CAT was −2 (8). On Cox regression analysis, baseline CAT score, change in CAT and history of exacerbation were independent risk factors for exacerbation in the one-year follow-up. Compared with the r value of correlation between baseline CAT score and frequency of exacerbations during the one-year follow-up (r = 0.286, p < .001), that correlation between the change in CAT and frequency of exacerbations during follow-up was higher (r = 0.421, p < .001). The receiver operating characteristic (ROC) curves showed that change in CAT had a better predictive capacity for future exacerbation than baseline CAT (0.789 versus 0.609, p = .001). The ROC showed that change in CAT also had a better predictive capacity for future exacerbation than exacerbation in the previous year (0.789 versus 0.689, p = .011). Conclusion The correlation between baseline CAT score and future exacerbation was weak, however, the correlation between change in CAT and future exacerbation was moderate. Change in CAT in the short term had a better predictive value for future exacerbations of COPD than baseline CAT and exacerbation in the previous year.


Introduction
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide [1]. Exacerbations are the key outcome of COPD patients, defined as exacerbations of respiratory symptoms leading to additional treatment [2]. Exacerbation of COPD will accelerate hospitalisation rates [3], increase mortality [4], reduce the quality of life [5,6]. Therefore, prevention of exacerbations is one of the important measures of COPD management strategies.
At present, there are many methods for predicting future exacerbations. Among them, the history of exacerbation is one of the most powerful predictors [7,8]. It is usually applied in clinical settings, but the disadvantage is that it is more subjective, leading to a higher missed diagnosis rate. Relevant studies have confirmed that the poor quality of life of COPD patients is associated with future exacerbations [6]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends the use of the COPD Assessment Test (CAT), which evaluates and quantifies the impact of COPD symptoms on the health of patients [9]. The CAT score observed at a point in time is a reliable indicator for predicting future exacerbations. Recent studies have shown that the higher the CAT score, the higher the risk of future exacerbations [10]. Jo et al. [11] indicated that a baseline CAT !15 can predict future exacerbations. However, the disease trajectory is also an important basis for predicting the risk of exacerbation. Recent research based on analysis of TORCH (Towards a Revolution in COPD Health) trial data, found that clinically important deterioration (CID) occurred within 6 months, including moderate to severe deterioration, a decrease of forced expiratory volume in 1 s (FEV1) or the deterioration of the total score of St George's Respiratory Questionnaire (SGRQ), is associated with an increased risk of long-term deterioration [12]. SGRQ is another questionnaire used to assess the health status of people with respiratory disease [13]. At the individual level, the investigator determined À2 units to be the minimal clinically important difference (MCID) of the change in CAT score, with an SGRQ change of À4 as an anchor [14]. Zhao et al. [15] found that the CID based on 2 points of CAT deterioration (CID-C) shows a good predictive value for the risk of exacerbation in the future. Therefore, short-term changes in CAT scores may be associated with the risk of exacerbation. However, there is no specific study to clarify the predictive value of changes in CAT for future exacerbations alone. Additionally, there is no research comparing the predictive value of baseline CAT score and change in CAT for future exacerbations. Therefore, the purpose of this study is to compare the predictive value of baseline CAT score and short-term change in CAT for future exacerbations of COPD.

Study design and subjects
This was a multicentre, prospective and observational study. All subjects were from the outpatient COPD database of the Second Xiangya Hospital of Central South University (ChiCTR-POC-17010431) from December 2016 to October 2020. According to GOLD 2017 guidelines, COPD was diagnosed when a ratio of FEV1 to forced vital capacity (FEV1/FVC) < 0.70 after inhaling a bronchodilator [16]. We excluded patients with a history of bronchiectasis, asthma, lung cancer or pneumonia, or severe heart, liver or kidney disease. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Second Xiangya Hospital of Central South University. All patients provided written informed consent.

Data collection and definition
Clinical characteristics included age, sex, education degree, body mass index (BMI), smoking history, biofuel and occupational exposure history, CAT, Modified Medical Research Council Dyspnoea Scale (mMRC), Clinical COPD Questionnaire (CCQ), pulmonary function, inhalation therapy drugs and exacerbations (moderate to severe) in the previous year; these were collected at baseline. As for smoking history, we defined "smoker" as smoking exposure more than 10 pack-years, "ex-smoker" as not less than 10 pack-years, but smoking cessation more than 6 months, "never smoker" as smoking exposure under 10 pack-years [17]. COPD disease severity was classified using the GOLD guidelines and was divided into four stages: I (FEV1 ! 80% predicted), II (FEV1 50-80% predicted), III (FEV1 30-50% predicted), or IV (FEV1 < 30% predicted). The total score of CAT ranges from 0 to 40. At the 6-month visit, the results of the CAT score, medication possession ratio (MPR) and exacerbations during the 6 months were recorded. Adherence was calculated using MPR. MPR was calculated by summing the days of medication supply provided and dividing by the total time treated. Adherence was classified as follows: Poor adherence (MPR < 80% or MPR > 120%) and Adherence [18]. Then, data on exacerbation over one year were collected at the 12-month follow-up.

Definition of baseline CAT score and change in CAT
Baseline CAT score was collected at baseline. Change in CAT was defined as CAT score changing between baseline and the 6-month follow-up.

Definition of exacerbation
Moderate exacerbation was defined as exacerbation of respiratory symptoms requiring antibiotics and/or oral corticosteroids; severe exacerbation was defined as exacerbations requiring hospitalisation or emergency room admission for more than 2 days. If the patient had at least two exacerbations or died during the follow-up period, they were recorded as experiencing a frequent exacerbation.
Statistical analysis SPSS 26.0 (IBM, Armonk, NY, USA) was used for statistical analysis of the data. Continuous variables were expressed as mean ± standard deviation or median and interquartile range as appropriate. Continuous variables that were normally distributed and showed homogeneity of variance were tested using Student's t-test; otherwise, non-parametric tests were used. The chi-square test was used for categorical variables. Association analysis was performed using Spearman's rank correlation coefficient. A multivariate Cox regression analysis was performed for identifying factors predicting exacerbation during oneyear follow-up, by including variables that were significant (p < .05) on univariate analysis. The multivariate stepwise logistic regression analysis was used to analyse the clinical features associated with the change in CAT. The ROC curve was calculated and the area under the curve (AUC) was compared using the Z-test. For all analyses, a p-value of <.05 was considered statistically significant.

Baseline characteristics
A total of 571 patients with COPD were initially enrolled. At a 6-month visit, 21 patients were excluded from the study due to loss of contact. At the 12month follow-up, 14 patients dropped out due to loss of contact. Finally, we recruited 536 patients for the final analysis ( Figure 1). Baseline demographic and clinical characteristics are shown in Table 1. Overall, 89.0% of patients were male, and the mean age of all patients was 64.0 ± 8.0 years. Most patients had a history of smoking exposure, with 38.6% being current smokers and 42.9% ex-smokers. The mean CAT score was 14.5 ± 6.6 and the median (IQR) FEV1% was 50.3 (28.8). The proportion of patients who experienced moderate to severe exacerbations in the previous year was 58.0% and 33.8% experienced frequent exacerbations. The distribution of inhalation therapy was as follows: LAMA(30.5%), LAMA/LABA (7.0%), ICS/LABA (9.6%), ICS/LABA/LAMA (51.0%), Others (1.6%) including ICS/LAMA, short-acting bronchodilators and no inhalation medication.

Characteristics during one-year follow-up
The mean CAT at 6-month follow-up was 12.2 ± 6.6, with a median (IQR) change in CAT of À2 (8) from baseline to 6-month follow-up. Of the 536 patients, 63.6% were with adherence to therapy, 21.5% of patients had at least one moderate to severe exacerbation during the 6-month follow-up. The median (IQR) number of exacerbations in a 6-month visit was 0 (1) ( Table 2). 36.0% had at least one moderate to severe exacerbation, 16.0% had frequent exacerbations, and 21.8% had severe exacerbations during 12-month follow-up ( Table 3). The median (IQR) number of exacerbations during the 12-month follow-up among patients with exacerbations in the previous year and no exacerbations in the previous year were 0 (1) and 0 (0), respectively (p < .001). In addition, patients with exacerbations in the previous year were more likely to suffer future exacerbation than patients with no exacerbation in the previous year (Table S1).

Correlation of baseline CAT score and change in CAT with future exacerbations
The study compared baseline CAT scores and changes in CAT between patients with different numbers and severity of exacerbations during one-year follow-up. As shown in Figure 2, the mean baseline CAT score of patients with exacerbation was higher than that of patients without exacerbation (p < .001). Additionally, it showed a different median change in CAT between the two groups; the CAT score of patients with exacerbation during one-year follow-up from 0 th to 12 th month had deteriorated at the 6-month follow-up compared to baseline but had decreased in the patients without future exacerbation [2 (6) versus À4 (7), p < .001]. Compared to patients without frequent exacerbations during the follow-up from 0 th to 12 th month, patients with frequent exacerbations had a higher mean baseline CAT (p < .001) and a worse change in CAT (p < .001) at the 6-month follow-up. However, patients with severe exacerbations showed no significant difference in baseline CAT (p > .05) compared to patients with non-severe exacerbations, but   they did show a greater CAT score deterioration at the 6-month visit (p < .001). As shown in Figure 3, both show a positive correlation with the frequency of future exacerbation. The correlation between baseline CAT score and frequency of exacerbations during the one year of follow-up is a week (r ¼ 0.286, p < .001), the correlation between change in CAT score and frequency of exacerbation during one-year follow up was moderate (r ¼ 0.421, p < .001).
By univariate Cox regression analysis, we accessed the risk factors associated with the occurrence of at least one exacerbation in the one-year follow-up. The meaningful predictive factors included FEV1% predicted, baseline CAT score, mMRC score, CCQ score, exacerbations in the past year, GOLD Grade, Change in CAT and MPR (Table 4). These variables were included in the multivariate Cox regression model. Finally, baseline CAT score [hazard ratio (HR): 1.082;  Table 5).
Comparation of the predictive value of CAT baseline value and change in CAT for future exacerbations ROC curves showed that change in CAT had a better predictive capacity for the occurrence of exacerbation than baseline CAT (0.789 versus 0.609, p < .001). The sensitivity for identifying exacerbation of change in CAT and baseline CAT score was 64.1% and 75.9%, and the specificity was 70.9% and 60.1%, respectively. In addition, change in CAT had a better predictive value for frequent exacerbation compared with baseline CAT score; the area under the ROC curve (AUC) was 0.805 and 0.611 (p < .001). Additionally, change in CAT also showed a better predictive capacity for severe exacerbation than baseline CAT; the AUC was 0.771 and 0.550 (p < .001) (Figure 4).

Comparison of predictive value of change in CAT and exacerbation in the past year for future exacerbations
We compared the value of change in CAT and exacerbations in the past year for predicting the occurrence of future exacerbation. As shown by Figure 5, ROC curves showed that change in CAT had a slightly better predictive value for the occurrence of exacerbation  than exacerbation in the past year (AUC ¼ 0.789 versus 0.689, p ¼ .011). The optimal cut-off for change in CAT value is 2. The patients were divided into groups with change in CAT ! 2 and change in CAT < 2.
Comparing the exacerbations in the previous year, there was no significant difference between the two groups ( Table 6).

The clinical characteristic associated with change in CAT
The change in CAT was divided into two groups according to the cut-off value. compared with patients with a change in CAT 2, the Baseline CAT score was slightly lower, more patients with mMRC ! 1, fewer patients with GOLD I, more patients with GOLD III, and more patients with poor medication adherence in patients with change in CAT ! 2 ( had a higher incidence of more than 2 scores worsening in a change in CAT (Table 7).

Discussion
To the best of our knowledge, this is the first prospective, observational study to compare the predictive value of the baseline CAT score and the change in CAT for future exacerbation. COPD exacerbation is one of the important events in the disease progression of COPD patients. A study showed that severe exacerbation is an independent risk factor for death [19]. Therefore, it is necessary to assess the risk of exacerbations. Recent research has shown that a history of exacerbations in the previous year was associated with a higher risk of future exacerbation [7,20]. This result is consistent with our research, in which patients with exacerbations in the past year were more likely to experience exacerbations during the one-year followup compared to those without a history of exacerbation. Besides, the study showed that history of exacerbation was one of the independent risk factors for future exacerbation on the multivariate Cox model. The research showed that patients who experience future exacerbation have a higher baseline CAT score than patients who do not, and there are similar phenomena seen in patients with frequent exacerbations and infrequent exacerbations. This result is in line with previous research [10,21], in which patients with a higher CAT score were at higher risk of exacerbation.
The study showed that the CAT scores at 6-month visits deteriorated from the baseline in patients with exacerbation during the one-year visit compared to patients without exacerbation. This phenomenon was also observed in patients with frequent and severe exacerbation. This is consistent with previous research showing that CID-C based on CAT deterioration was associated with the risk of future exacerbation [15]. This reflects that the occurrence of short-term CAT deterioration may be associated with future exacerbations. In addition, studies of Claus et al. [22] have regarded a short-term deterioration in CAT greater than 2 points as a part of CID of COPD patients to assess changes in disease status over 20 weeks. The research found that not only history of exacerbation and CAT score, but also change in CAT were also one of the independent risk factors for future exacerbation on multivariate Cox model, this is a new discovery that is different from CID to predict future exacerbation.
Moreover, this study found that baseline CAT value has a positive correlation and predictive value for future exacerbation risk. This is consistent with the previous results, in which a CAT score over 15 is a good model for predicting exacerbations in the future, with an AUC of 0.610 [11]. In addition, the study showed that change in CAT was also positively correlated with the frequency of exacerbation in the oneyear follow-up. Change in CAT can not only predict the possibility of future exacerbation and frequent exacerbation, but also the risk of severe exacerbation. Therefore, these results showed that in addition to the health status at a time in point, the changes in health status may be also an important basis for predicting future exacerbations. This is consistent with the study by Naya et al. [14], in which CID containing SGRQ for assessment of a healthy quality of life over 6 months was also associated with future exacerbation. The difference is that our study is the first to analyse the relationship between changes in CAT scores and future exacerbations separately. Also, the change in CAT value had a higher r value and a better predictive value for future exacerbation than the baseline CAT score in the study, which represents a novel discovery.
History of exacerbations has been widely used to assess future exacerbations, but it relies on the subjective recollection of patients, leading to misdiagnosis and missed diagnosis. Therefore, a more objective and  effective basis is needed for clinical treatment. The study analysed the predictive value of exacerbation in the past year, demonstrating an AUC of 0.698 (p < .001). It is consistent with the previous research, in which the exacerbation in the past year had predictive capacity for future exacerbation, with an AUC of 0.609 [21]. Further analysis of our research found that the change in CAT has better predictive value for future exacerbations than exacerbation in the previous year. History of exacerbations is an important basis for evaluation of the disease and treatment [23]. However, short-term activity trajectories can better reflect the current status of the disease. CID can be used to assess the early deterioration of the COPD trajectory and can provide useful information on how to maintain patient stability [12,24]. At present, more and more research is being devoted to drugs for the prevention and treatment of CID, so as to prevent disease deterioration [25][26][27].
The study also analysed the clinical feature in the different changes in the CAT group, it indicated GOLD stage II, III and medication adherence were significantly associated with a change in CAT in logistic regression analysis. Previous studies have reported that patients with high GOLD stage were more likely to experience disease exacerbations [28], and CAT scores increased when they experienced exacerbations [29]. In this study, only GOLD II and III were associated   with a change in CAT in this study, GOLD grade IV was not a related factor for the deterioration of CAT, which deserves further study. Moradkhani B et al [30] showed that patients with high quality of life were more adherent to their medications, therefore patients with poor adherence would develop deterioration of CAT scores in short term. CAT is a common clinical test used to assess the health status of COPD patients. As a part of CID, change in CAT can be more objective and simple to reflect short-term disease status compared with the evaluation three parts in CID. Therefore, change in CAT can be observed as health status changes to provide clinicians with a more objective and reliable clinical measure to predict the risk of disease aggravation.
There are some limitations of this study. Firstly, we established a good predictive value of changes in CAT in one cohort but lacked another cohort to verify our model. Secondly, although this study also shows the change in CAT has better predictive value for future exacerbation than the history of exacerbation, it does not compare the value of a series of measurements and a single current measurement associated with the trajectory of disease to predict the risk of exacerbation. Since our study uses an ongoing prospective design, further studies can be carried out.

Conclusion
In summary, our results revealed that a higher baseline CAT score and worse change in CAT in the short term were associated with a higher risk of future exacerbation. The correlation between baseline CAT score and future exacerbation was weak, however, the correlation between change in CAT and future exacerbation was moderate. Short-term change in CAT had a better predictive value for future exacerbations of COPD than baseline CAT and exacerbation in the previous year.